Abstract
Abstract Large granular lymphocytes (LGL) are a lymphoid subset that consists of 10-15% of peripheral blood mononuclear cells. LGL can be divided into (2) major lineages of CD3- NK cells and CD3+ T Cells. Symptoms may include rheumatoid arthritis and neutropenia which leads to recurrent bacterial infections. The sphingolipid metabolism pathway has been found to be deregulated in NK-LGL leukemia. Glucosylceramide synthase (GCS), a key component of this pathway is an enzyme that catalyzes the conversion of proapoptotic ceramide to inactive glucosylceramide by transferring a glucose residue from UDP-glucose to ceramide. GCS has been found to be upregulated in cancer cells and its overexpression has been associated with multidrug resistance in leukemia cells. Both rat and human leukemic LGL cells have been treated with a combination treatment targeting two key components of the sphingolipid pathway. One of the agents in use is the C6-ceramide (C6) nanoliposome which has led to caspase-dependent apoptosis in a time- and dose-dependent manner. Systemic i.v. delivery of nanoliposomal ceramide led to complete remission in 5/14 syngeneic Fischer F344 rat model of NK-LGL leukemia. However a greater response will be achieved by combination treatment of C6 and through targeting a second key component of ceramide metabolism with DL-threo-1-Phenyl-2-palmitoylamino-3-morpholino-1-propanol (PPMP). PPMP is a GCS inhibitor that prevents the endogenous ceramide already present in the cell from being glycosylated into its inactive form where it can no longer induce cell death. Overall, this combination treatment shows a synergistic effect with increase of ceramide levels in order to induce apoptosis and therefore death of these persistent LGL cells. Cell flow cytometry examining 7AAD/Annexin V staining has shown ∼80% apoptosis when 6.25 uM C6 ceramide and 15 uM PPMP are used in combination on aggressive rat LGL cells. Whereas, only ∼19% is observed with C6 and ∼17% of PPMP are observed individually in treatment. Overall, apoptosis appeared increased in a dose response manner after treatment with PPMP and C6. This is a significant finding of P<0.005, when compared to DMSO and ghost nanoliposome controls which only induce ∼15% apoptosis. In addition, this combination treatment has been utilized on normal human peripheral blood mononuclear cells where only 11.2% apoptosis was induced and 9% in the normal spleen mononuclear cells in rats. As a result, this combination treatment appears promising in specifically targeting LGL cells while sparing normal cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4302. doi:10.1158/1538-7445.AM2011-4302
Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
